1. Field of Invention
The present invention relates generally to a method of producing particles from solution-in-supercritical fluid or compressed gas emulsions. More particularly, the present invention relates to a method of producing particles by spraying a solution-in-supercritical fluid or compressed gas emulsion into spray droplets and removing solvent from the spray droplets to form particles.
2. Description of Related Art
Conventional methods for producing drug particles include spray drying and jet milling. The typical spray drying technique involves spraying a solution of a solute material dissolved in a solvent into droplets and then evaporating the solvent from the droplets using hot air to form particles of the solute material. The particles obtained by spray drying typically have a broad size distribution, with the average particle size of the particles being in the micron range.
The jet milling technique involves accelerating particles in a stream of air to cause a reduction in particle size due to inter-particle collisions. Jet milling tends to produce an undesirably broad distribution of particle sizes, with only a fraction being less than 1 micron in diameter. Moreover, the shearing energy required for jet milling can degrade some biologically active materials and polymers.
Nanometer sized particles (hereinafter sometimes referred to simply as nanoparticles”) have also been produced from emulsions using techniques such as emulsion evaporation and solvent extraction of emulsions. One of the drawbacks associated with the emulsion evaporation process is that the process proceeds at an undesirably slow rate, which exceeds four hours in some instances. Moreover, some of the organic solvents used in the emulsion extraction process give rise to concerns about possible environmental and health affects due to residual solvent in the resulting particles.
The solvent extraction of emulsions technique requires large amounts of solvent for extraction, which leads to large waste streams, increased cost and concerns about residual solvent toxicity.
Another technique, which is sometimes referred to as dilution by water of oil-in-water (O/W) emulsions prepared using partially water soluble organic solvents, can also be used to obtain small particles. Unfortunately, this technique can result in low nanoparticle concentrations in the final dispersion. It also uses undesirably large quantities of water.
The vacuum distillation of emulsions has also been used to produce particles. Unfortunately, the associated high operating cost makes this process economically undesirable. In addition, the processing times required for achieving a low residual solvent content in the resultant particles produced by this method is still lengthy and may cause emulsion instability.
Conventional supercritical fluid based methods for nanoparticle production include the following techniques: Rapid Expansion of Supercritical Solution (RESS), Supercritical Anti-Solvent (SAS), Gas Anti-solvent (GAS) and Aerosol Solvent Extraction System (ASES).
RESS involves precipitation of particulate material by expansion of solution of the material dissolved in supercritical fluid. Therefore, application of the process is limited to materials that are substantially soluble in the supercritical fluid (typically higher than 104 mole fraction).
In the SAS process, which can be operated as a continuous or a batch process, a solution containing a solute of interest dissolved in a solvent is injected into a vessel containing a supercritical fluid. Extraction of the solvent from the injected solution by the supercritical fluid leads to precipitation of the solute as particles.
GAS is a batch process whereby supercritical fluid anti-solvent is injected into a solution containing the solute to be precipitated. GAS is analogous to evaporative crystallization in some circumstances. The supercritical fluid extracts the solvent out of the solution, which causes the solid to precipitate as particles.
ASES is a continuous process for precipitating particles. The solution of interest is injected via a nozzle into a supercritical fluid stream. The supercritical fluid stream is co-injected, for example, a coaxial nozzle arrangement is used so that the inner nozzle injects the solution, and the outer nozzle injects the supercritical fluid. Alternatively, a single nozzle can be used to inject both the supercritical fluid and the solvent. Such a system is described in U.S. Pat. No. 6,372,260, which is hereby incorporated by reference in its entirety.
Unfortunately, the particle formation techniques described above generally tend to exhibit poor particle size control and uniformity. In most cases, the processes produce particles that are greater than 1 micron in diameter. This fundamental limitation is caused by the particle precipitation mechanisms. The competition between nucleation and growth phenomena creates a limitation on a mean particle diameter for each of the above conventional processes. Accordingly, it is difficult to obtain nanosized and single digit micron-sized particles for most materials, and such particles generally have an undesirably broad particle size distribution.
Carbon dioxide-Assisted Nebulization with Bubble Drying (CAN-BD) is another processing technique for producing particles using a supercritical fluid. A CAN-BD process is disclosed in U.S. Pat. No. 5,639,441, which is hereby incorporated by reference in its entirety. In CAN-BD, the solubility of supercritical or compressed CO2 in water or organic solvents is used to generate small droplets or bubbles, and hot air or nitrogen is used to evaporate the solvent and form solid particles. The CAN-BD method is simple, and allows for-the processing of water-soluble compounds without use of organic solvents.
CAN-BD uses a reduced processing temperature relative to conventional spray-drying processing temperatures. Unfortunately the particles produced using this technique are usually in the micron range and have a broad size distribution. The high operating temperature also makes the process unsuitable for processing of certain proteins.
In view of the limitations of prior art processing methods, it would be desirable to provide a processing technique whereby particles could be produced having a relatively small particle size in a narrow size distribution range, at a comparatively reduced processing time and at reduced cost. It would be also be desirable to develop a process that produces particles without using undesirably large amounts of solvent. Further, it would be desirable to have a technique that provides a highly controllable means of adjusting the size of the resultant particles over a wide range.